The Synthesis Core (Core C) provides enabling technology vital to the UCSF Cystic Fibrosis Research and Translation Core Center. The objective of this Center is to discover and evaluate novel small-molecule therapies for cystic fibrosis (CF), and the Synthesis Core will figure prominently in this effort by performing targeted and small molecule library synthesis. Synthesis Core interactions with investigators in the Center are categorized by three levels of service. The first level involves lead optimization and exploration of structure? activity relationships (SAR) by exhaustive synthesis, as has been done in the current award for ?F508-CFTR correctors and potentiators. This level of participation is anticipated for ?F508-CFTR correctors and potentiators, as well as for TMEM16A activators, CaCC activators, and P. aeruginosa C12-inhibitors. Depending on High-Throughput Screening (HTS) Core discovery progress, as well as the importance of focused chemistry in meeting Center goals, this level of involvement may also be warranted for additional projects. Re-synthesis of lead compounds, provision of medicinal chemistry advice, and SAR analysis is the second level of Core C involvement in the Center, and many projects will benefit from this level of service. The last level of service consists of providing compounds that have already been synthesized (including inhibitiors and activators of CFTR and TMEM16A) as well as providing advice on the medicinal chemistry of active compounds. The Synthesis Core will also work closely with the HTS Core to verify the identity of hits and validate hit activity by hit re-synthesis and spectroscopic characterization. All lead compounds supplied by the Synthesis Core for project and Core activities will be highly purified (generally at ~95%).